Citations

Abstract Introduction Periacetabular osteotomy (PAO) is a well-established procedure for hip preservation, traditionally performed on conventional radiolucent tables that provide rigid support to the lower extremity. The Pivot Guardian™ Distraction System extension was recently introduced to facilitate concomitant hip arthroscopy and PAO, enhancing surgical efficiency. However, flexible leg support may alter the biomechanical stability of the pelvis during osteotomy cuts, particularly the ischial osteotomy. This study compared intraoperative and perioperative outcomes of PAOs performed with the Guardian Table extension to those performed on conventional radiolucent tables. Methods All PAOs performed by one surgeon since the introduction of the guardian extension were reviewed. Seventy-two PAO cases were identified; 26 were performed on a Guardian table concomitantly with arthroscopic procedures, while 46 were performed on a conventional radiolucent Demographic variables, surgical characteristics, intraoperative complications and perioperative outcomes were compared between the groups. Groups were comparable in age, BMI, smoking status, history of previous hip arthroscopy, and primary diagnoses. Results The use of the Guardian extension had a higher proportion of women (96.2% vs. 73.9%, p=0.018) and longer operative times due to the addition of the hip arthroscopy (170 ± 54 vs. 90 ± 18 min, p < 0.0001). Notably, intraoperative posterior column fractures only occurred with the use of the Guardian table (15.4% vs. 0%, p=0.0062). No other identifiable risk factors contributed to this finding. Fractures were diagnosed based on intraoperative fluoroscopic images, or immediate postop X-rays, or X-rays at the first follow up. Rates of other complications were similar between the two groups. Conclusion While the Guardian Table extension facilitates simultaneous arthroscopic procedures in the context of PAO procedures, its use was associated with an increased risk of intraoperative posterior column fractures. This may be due to the flexible structure of the leg extension component. Surgeons should be aware of the flexible nature of the table and plan for intraoperative stabilization of the distal portion to increase rigidity.

Abstract Background: Oncogenic alterations (gene amplification, mutation, and fusion/rearrangements) of fibroblast growth factor receptor 2 (FGFR2) are rare and occur at varying frequencies across solid tumor types and have become critical therapeutic targets in drug development. First generation FGFR pan-kinase inhibitors non-selectively inhibit FGFR1-4 and are associated with dose limiting toxicities and narrow therapeutic windows. Off-isoform toxicity (FGFR1-hyperphosphatemia; FGFR4-diarrhea) and on-target acquired resistance have led to limited efficacy, which is primarily seen in FGFR2-fusion+ intrahepatic cholangiocarcinoma. Therapies that selectively target FGFR2 remain an unmet need in advanced breast cancer as well as other solid tumor types. RLY-4008 is a novel, oral FGFR2 inhibitor designed to overcome the limitations of pan-FGFR inhibitors (FGFRi) by potently and selectively targeting primary oncogenic FGFR2 alterations and acquired resistance mutations. RLY-4008 is > 200-fold selective over FGFR1, > 80- and > 5000-fold selective over FGFR3 and FGFR4 respectively. Here we describe a phase 1/2 study to investigate the safety and antitumor activity in advanced FGFR2 altered cancers, including breast cancer. Methods: ReFocus is a phase 1/2 open label global study evaluating the safety and efficacy of RLY-4008 (NCT04526106) in adult patients with advanced unresectable and/or metastatic cancers harboring an FGFR2 alteration. Key eligibility criteria include: documented FGFR2 alteration in blood or tissue per local assessment, ECOG performance status of 0-1, disease that is refractory or not adequately responding to standard therapy, has no available standard therapy, or patient is intolerant of, or declined standard therapy (including pan-FGFRi), and measurable or evaluable disease per RECIST 1.1. FGFR2 alteration will be confirmed retrospectively by central laboratory assessment. Part 1 dose escalation employed the Bayesian Optimal Interval (BOIN) design to determine the MTD/RP2D of RLY-4008. Part 2 dose expansion is presently enrolling patients at the RP2D of RLY-4008 and includes 5 cohorts comprised of patients with: 1. FGFR2 fusion+ cholangiocarcinoma previously treated with an FGFRi; 2. FGFR2 fusion+ cholangiocarcinoma not previously treated with an FGFRi; 3. FGFR2 fusion+ solid tumors; 4. FGFR2 mutation+ solid tumors and 5. FGFR2 amplified solid tumors. Solid tumors in cohorts 3, 4 and 5 will have a focus in breast cancer. The primary endpoint is objective response rate (ORR); key secondary endpoints include: duration of response, safety and tolerability, correlation of FGFR2 genotype by central tissue assessment with antitumor response, characterization of PK profile, and quality of life. US enrollment began September 2020 and has expanded into Europe and Asia. Clinical trial information: NCT04526106. Citation Format: Suneel Kamath, David Tai, Irene Moreno, Hani Babiker, Zhaohui Jin, Changhoon Yoo, Fabien Ricard, Kai Yu Jen, Jim Coward, Jia Liu, Frans Opdam, Michael Millward, Mariano Ponz-Sarvise, Jeffrey Yachnin, Richard Kim, Joon Oh Park, Vivek Subbiah, Alison M. Schram. ReFocus: A Phase 1/2 Study of the Highly Selective FGFR2 Inhibitor, RLY-4008, in Patients with Advanced Solid Tumors Including Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-24-01.

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

PURPOSE This phase I/II study evaluated tremelimumab (anticytotoxic T-lymphocyte–associated antigen-4 monoclonal antibody) and durvalumab (antiprogrammed death ligand-1 monoclonal antibody) as monotherapies and in combination for patients with unresectable hepatocellular carcinoma (HCC), including a novel regimen featuring a single, priming dose of tremelimumab (ClinicalTrials.gov identifier: NCT02519348 ). PATIENTS AND METHODS Patients with HCC who had progressed on, were intolerant to, or refused sorafenib were randomly assigned to receive T300 + D (tremelimumab 300 mg plus durvalumab 1,500 mg [one dose each during the first cycle] followed by durvalumab 1,500 mg once every 4 weeks), durvalumab monotherapy (1,500 mg once every 4 weeks), tremelimumab monotherapy (750 mg once every 4 weeks [seven doses] and then once every 12 weeks), or T75 + D (tremelimumab 75 mg once every 4 weeks plus durvalumab 1,500 mg once every 4 weeks [four doses] followed by durvalumab 1,500 mg once every 4 weeks). Safety was the primary end point. Secondary end points included objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors v1.1 and overall survival; exploratory end points included circulating lymphocyte profiles. RESULTS A total of 332 patients were enrolled (T300 + D, n = 75; durvalumab, n = 104; tremelimumab, n = 69; and T75 + D, n = 84). Tolerability was acceptable across arms, with grade ≥ 3 treatment-related adverse events occurring in 37.8%, 20.8%, 43.5%, and 24.4%, respectively. Confirmed ORRs (95% CI) were 24.0% (14.9 to 35.3), 10.6% (5.4 to 18.1), 7.2% (2.4 to 16.1), and 9.5% (4.2 to 17.9), respectively. An early expansion of CD8+ lymphocytes was associated with response across arms, with highest proliferating CD8+ lymphocyte levels occurring in the T300 + D arm. The median (95% CI) overall survival was 18.7 (10.8 to 27.3), 13.6 (8.7 to 17.6), 15.1 (11.3 to 20.5), and 11.3 (8.4 to 15.0) months in the T300 + D, durvalumab, tremelimumab, and T75 + D arms, respectively. CONCLUSION All regimens were found to be tolerable and clinically active; however, the T300 + D regimen demonstrated the most encouraging benefit-risk profile. The unique pharmacodynamic activity and association with ORR of the T300 + D regimen further support its continued evaluation in HCC.

4508 Background: The combination of dual immune checkpoint inhibitors (ICI) T (anti–CTLA-4) and D (anti–PD-L1) showed tolerability with a promising objective response rate (ORR) in the initial cohort of this study (NCT02519348). Subsequent evaluation of pts with solid tumors treated with increasing doses of T suggested priming with a higher dose of T may induce a stronger immune response and enhance anti-tumor activity. Thus, the randomized expansion cohorts comprised 4 arms evaluating T and D as monotherapies and 2 T+D regimens, including a novel T+D regimen featuring a single, priming dose of T. Methods: ICI-naïve pts with aHCC who progressed on, were intolerant to, or refused sorafenib were randomized to one of two T+D combinations: T300+D (T 300 mg + D 1500 mg 1 dose followed by D Q4 weekly [Q4W]) or T75+D (T 75 mg Q4W + D 1500 mg Q4W [4 doses] followed by D Q4W); or single agent D (1500 mg Q4W) or T (750 mg Q4W). Safety was the primary endpoint. ORR by blinded, independent central review using RECIST v1.1, duration of response (DoR), circulating lymphocytes, and overall survival (OS) were assessed. Results: At data cut-off (09/02/2019), 332 pts were enrolled. Median follow-ups were 11.7 months (mo) for T300+D, 14.6 (T75+D), 8.9 (D), and 15.8 (T). Treatment-related adverse event (trAE) incidences are shown (Table); no deaths were attributed to trAEs for T300+D or T. The T300+D arm had the highest confirmed ORR (DoR not reached [NR]) and longest OS (Table). A unique proliferative T cell profile was identified for pts in the T300+D arm, suggesting additive biologic activity for the combination, and showed pts with an OR exhibited high cytotoxic (CD8) counts. Conclusions: The encouraging clinical activity and tolerable safety profile suggest T300+D provides the best benefit-risk profile as opposed to T75+D or monotherapies. The unique pharmacodynamic activity of the T300+D regimen further supports its use in aHCC. T300+D and D are being evaluated in the ongoing phase III HIMALAYA study (NCT03298451) in first-line HCC vs sorafenib. Funding: AstraZeneca. Clinical trial information: NCT02519348 . [Table: see text]